Over the years, there have been many successful uses of polymers in medicine. Most of these applications require minimal polymer cell interactions. Consequently, there has been a lot of work done on minimizing the interactions of these polymer systems with the cells that they come in contact with.
However, one challenge in the area of biomedical materials that has received less attention is the development of substrates that can interact favorably with mammalian cells either in vitro or in vivo. Such materials could be useful for many applications from the basic study of how cells interact with surfaces to applied areas such as in vitro mammalian cell culture for the production of useful materials and in vivo cell transplantation for replacement of lost cellular function.
To illustrate the need for in vivo cell transplantation, it is worth considering that the success of whole organ transplantation is limited by donor organ availability. As an example, transplantation of the liver is often times successful but has plateaued at about 2200 transplants per year because of donor scarcity. Unfortunately, 30,000 Americans die every year of liver disease while an additional 5 million Americans are affected. The cost to the economy is more than $14 billion dollars annually. The situation is similar with other organ systems such as the kidney, pancreas, lung, and heart.
The demand for replacement organs is therefore very high. However, since the function of most of these organs is so complex and in most cases not yet completely understood, synthetically recreating their function is practically impossible. Alternative treatments concentrate on manipulating the smallest functional unit of the organ, the individual cell. Many groups have attempted cell transplantation under a variety of conditions (Bumgardner, G. L.; Fasola, C.; and Sutherland D. E. R., "Prospects for Hepatocyte Tranplantation," Hepatology, 8, 1158-1161 (1988); Wong, H. and Chang, T. M. S.. "The Viability and Regeneration of Artificial Cell Microencapsulated Rat Hepatocyte Xenograft Transplants in Mice," Biomat., Art. Cells, Art. Org., 16, 731-739 (1988); Vacanti, J. P.; Morse, M. A.; Saltzman, M.; Domb, A. J.; Perez-Atayde, A.; and Langer, R., "Selective Cell Transplantation Using Bioabsorbable Artificial Polymers as Matrices," Journal of Pediatric Surgery, 23, 3-9 (1988); U.S. Pat. No. 4,696,286 to Cochrum (1987); Dawson, R. M.; Broughton, R. L.; Stevenson, W. T. K.; and Sefton, M. V., "Microencapsulation of CHO Cells in a Hydroxyethyl Methacrylate-Methyl Methacrylate Copolymer," Biomaterials, 8, 360-366 (1987); Jaffe, V.; Darby, H.; and Selden, C., " The Growth of Transplanted Liver Cells within the Pancreas," Transplantation, 45, 497-498 (1987); Ricordi, C.; Flye, M. W.; and Lacy, P. E., "Renal Subcapsular Transplantation of Clusters of Hepatocytes in Conjunction with Pancreatic Islets," Transplantation, 45, 1148-1151 (1987); Sun, A. M.; Cai, Z.; Shi, Z.; Ma, F.; and O'Shea, G. M., "Microencapsulated Hepatocytes: An in vitro and in vivo Study," Biomat., Art. Cells, Art. Org., 15, 483-496 (1987); Sun, A. M.; O'Shea, G. M.; and Goosen, M. F. A., "Injectable Microencapsulated Islet Cells as a Bioartificial Pancreas," Applied Biochemistry and Biotechnology, 10, 87-99 (1984); Lim, F., "Microencapsulation of Living Cells and Tissues," Applied Biochemistry and Biotechnology, 10, 81-85 (1984)). When suspensions of cells have been injected, only small numbers survived. In addition, the cells that did survive had inadequate three dimensional structure and no way to form an appropriate structure. Some researchers have encapsulated cells, and this procedure provides excellent protection from the host's immune system. Often times, however, the barrier is too large and does not allow for sufficient exchange between the vascular supply and the cells. Moreover, the body sometimes forms a fibrous capsule around the implant which creates an additional barrier to the flow of nutrients. These approaches have had varying levels of success, but none has yet produced a viable clinical solution to the need for organs for transplantation.
Clinical success in the area of cell transplantation depends on efficiently using the available donor material and providing an environment conducive to long-term cell survival, differentiation and growth. One promising approach is to attach isolated cells and cell clusters onto synthetic biodegradable polymer scaffolds in vitro and then to implant the polymer-cell scaffold into recipients thereby replacing whole organ function with this device (Vacanti, J. P. "Beyond Transplantation, Third Annual Samuel Jason Mixter Lecture," Archives of Surgery, 123, 545-549 (1988)). With this approach, several implants could be obtained from each donor organ or cell material obtained from living donors. This could also help eliminate the need for immunosuppressive therapy, which is often required following organ transplantation.
The key to the success of this cell transplantation technique is in the design of the synthetic polymer scaffold (Cima, L., Ingber, D., Vacanti, J., and Langer, R. Hepatocyte Culture on Biodegradable Polymeric Substrates, Biotech. Bioeng., 38, 145-158, 1991; Cima, L.,, Vacanti, J., Vacanti, C., Ingber, D., Mooney, D., and Langer, R., "Tissue Engineering by Cell Transplantation Using Degradable Polymer Substrates," J. Biomech. Eng., 113, 143-151, 1991). This scaffold has several functions. First it must provide for active polymer/cell interactions for most mammalian cells must adhere to a surface in order to survive. It is also essential that this adhesion occur in such a manner that the cells continue to function normally. If the cells survive, but do not function normally, transplanting them into a patient is futile. Next, the polymer scaffold must have suitable surface chemistry to guide and reorganize the cell mass. Finally, the three dimensional structure must be designed to deliver a significant number of cells while allowing for the proper diffusion of nutrients.
Several criteria can be used to define the ideal substrate. Biocompatibility is essential in order to prevent acute adverse tissue responses that could impair the function of the transplanted cells. Biodegradability is desired to provide a completely natural tissue replacement without the possibility of chronic tissue reaction to the foreign body. The mechanical properties must allow for easy and reproducible processing into a variety of shapes, and the resulting devices must maintain their shape once implanted. Finally, the surface chemistry must be easily manipulated so that it can be optimized to meet the needs of each application.
One possible family of matrices that is commercially available consists of the purified extracellular matrix components, such as fibronectin, laminin, and collagen. Although these matrices provide great biocompatibility and cell adhesion, they do not have sufficient mechanical properties to build a stable three dimensional structure independent of the cells. It is also difficult to obtain high quality matrix material on a consistent basis since it must be harvested from natural sources.
Another possible matrix material that is produced commercially is surgical suture material. This is made from polyglycolic acid, polylactic acid and copolymers of glycolic and lactic acid. The biocompatibility and biodegradability of these polymers are well characterized, and the physical strength and fiber forming properties are good (Gilding, D. K. and Reed, A. M., "Biodegradable Polymers for Use in Surgery--Polyglycolic/Poly(lactic acid) Homo- and Copolymers: 1, Polymer, 20, 1459-1464 (1979); U.S. Pat. No. 4,048,256 to Casey, D. J. and Epstein, M., "Normally-Solid, Bioabsorbable, Hydrolyzable, Polymeric Reaction Product," (1977); Craig, P. H.; Williams, J. A.; Davis, K. W.; Magoun, A. D.; Levy, A. J.; Bogdansky, S.; and Jones, J. P. Jr., "A biologic Comparison of Polyglactin 910 and Polyglycolic Acid Synthetic Absorbable Sutures," Surgery, 141, 1-10 (1975); Frazza, E. J. and Schmitt, E. E., "A New Absorbable Suture," J. Biomed. Mater. Res. Symposium, 1, 43-58 (1971)). Also, since these polymers are used as suture material, they have already been approved for implantation. Unfortunately, the surface of these materials cannot be easily manipulated to provide optimal surface chemistry that could meet the needs of cells for each application.
A polymer is needed that has the beneficial qualities of polylactic acid but also provides for an easily manipulated surface chemistry.
It is therefore an object of the present invention to provide a biodegradable, biocompatible polymer modified to increase cell adhesion.
It is a further object of the present invention to provide such a polymer that has the physical and mechanical properties that allow the polymer to be processed into a matrix suitable for seeding with cells and implantation into a patient using standard surgical techniques.